The overall aim of this project is to determine the contribution of genetic variants to age at onset and risk of Alzheimer's disease (AD) in adults with Down syndrome (DS). Linkage and association studies have provided evidence for significant genetic influences on risk for AD, but the role for most of these genetic factors has not been investigated in adults with DS. Adults with DS over-express the p amyloid precursor protein (APP), have early onset of AD neuropathology and high risk for dementia. However, there is a wide range of age at onset of AD and not all adults with DS develop AD, suggesting the importance of additional determinants of risk. In previous work, we made several key observations that support the hypothesis that genetic and environmental factors can contribute to age at onset and risk of AD in DS. We propose now to determine the contribution of genetic variants that may influence cognitive function, risk for AD, age at onset of AD, and differences in AB peptide levels in a large cohort of adults with DS from our current project. We will take advantage of the deep phenotyping and repeated assessments that have been accomplished since the inception of this study. The cohort has completed up to 6 follow-up assessments and we have a large sample of incident AD cases whose onset and progression has been well documented. We have stored DNA, neuropsychological and functional status test scores, medical history, AP peptide levels, and dementia status on 366 men and women with DS and will recruit and follow an additional 150 nondemented participants in conjunction with Subprojects 1 and 2. Thus, we are in a unique position to relate genetic variants to a range of AD-related phenotypes. We will conduct an analysis of a broad panel of candidate genes for AD in adults with DS. We will fine map candidate genes using the lllumina GoldenGate custom array. Analyses will focus first on variants which have been identified in prior genome wide linkage or association studies, in meta-analyses, and that have been implicated in AD pathogenesis, including regions that are biologically important to screen, as well as candidate genes on chromosome 21 which are triplicated in adults with DS. We will perform allelic and genotypic association studies to identify polymorphisms that confer the strongest influence on (1) risk for AD; (2) age at onset of AD; (3) levels and rate of change in AB peptides in demented and nondemented adults; and (4) cognitive function. Then we will use the SNPs with robust significant associations with AD to confirm the associations in independent replication datasets, first in a large well characterized cohort of adults with DS and then in non-DS cohorts from the National Institute on Aging- Late Onset Alzheimer's Disease Study (NIA-LOAD). We will relate variants in genes identified in Dr. Tycko's epigenetic project to blood-related phenotypes.